PROJECT SUMMARY/ABSTRACT Symptoms of major depression and anxiety are a critical contributor to the overall disability in patients with epilepsy and are associated with significantly lower rates of seizure freedom. Since depression in epilepsy can arise either before or after the onset of seizures, many have proposed the presence of shared etiological disease mechanisms that simultaneously elevate seizure risk and result in mood impairments with anhedonia. The neuroanatomical and molecular mediators of this comorbidity are poorly understood. Developing specific treatment strategies to ameliorate these disease mechanisms may coordinately address ?ictal? (seizure- related) and ?interictal? (in between seizures) disability in a variety of epilepsy syndromes. This proposal tackles this issue in the context of temporal lobe epilepsy, the most common form of epilepsy in adults, using a combination of genetic mouse models, molecular tools and long-term home cage monitoring. The central hypothesis of this proposal is that hyperactivity within neurons of the ventral CA1 region of the hippocampus coordinately elevate seizure risk and produce depression-related symptoms. In Aim 1, the candidate will employ a targeted chemogenetic approach in mice to examine how hyperactivity within these neurons may impact depression-related behavior and seizure threshold. In Aim 2, using wireless electroencephalography, the candidate will examine how selectively inhibiting these neurons might improve seizure burden and interictal depression-like symptoms in a genetically valid mouse model of temporal lobe epilepsy and comorbid depression. To quantify the pervasive psychomotor alterations and neurovegetative derangements associated with depression-like syndromes, measurements of mouse behavior will be conducted within instrumented home cage chambers designed to capture unbiased prolonged measurements (>23h) of multiple behavioral variables while minimizing human contact. The candidate is an epileptologist with prior training in mouse models of depression, anxiety and autism spectrum disorders. This proposal will be mentored Dr. Jeffrey Noebels, an internationally renowned physician-scientist with expertise in the neuroqenetics of epilepsy who has a strong track record of independent NIH funding and K mentorship. All experiments will be conducted within the facilities of the Baylor College of Medicine, a highly ranked health sciences university with an established reputation in the field of biomedical research. The candidate?s professional development and training plan builds towards a career as a physician-scientist in the field of epilepsy psychiatric comorbidities, and specifically incorporates gap-based training in wireless electroencephalography and various advanced statistical techniques. Dr. Dennis Cox, Professor of Statistics at Rice University, will serve as a statistical consultant. The completion of these aims will shed new light into the (i) function of specific temporal lobe pathways that play roles in seizure generation and emotional behavior, and (ii) novel pathophysiology-based treatment strategies that are designed to address the disability of epilepsy across the ictal-interictal spectrum.